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PubMed2001

A study of mechanisms underlying amitriptyline-induced acute lung function impairment.

In this study possible mechanisms underlying the vaso- and bronchoconstriction caused by the tricyclic antidepressant drug amitriptyline in isolated rat lungs were investigated. Some features here are similar to those apparent in adult respiratory distress syndrome and acute lung injury. Amitriptyline exposure (50 and 100 microM) caused a dose-related, pronounced, and rapid vaso- (50 microM, 30 min, p < 0.001 and 100 microM, 30 min, p < 0.001) and bronchoconstriction (50 microM, 30 min, p = 0.01 and 100 microM, 30 min, p < 0.001). The maximal noted decrease in perfusion flow was 28 +/- 2.9% at 25 min and 80 +/- 4.5% at 30 min for 50 and 100 microM amitriptyline, respectively. The maximal noted decrease in airway conductance was 29 +/- 4.7% at 25 min and 68 +/- 5.0% at 30 min. To investigate mechanisms thought to be involved in amitriptyline-induced lung function impairment, lungs were treated with several different substances including antiinflammatory agents, antioxidants, inhibitors of enzymes involved in the arachidonic acid cascade, physiological antagonists, and neurogenic antagonists. A significant reduction of amitriptyline-induced vasoconstriction was observed when lungs were treated with the protein kinase inhibitor staurosporine (3 microM, 30 min, p < 0.001), the NO-donor S-nitrosoglutathione (100 microM, 30 min, p < 0.001) and the combined endothelin A/endothelin B receptor antagonist PD 145065. This latter inhibitor caused a significant attenuation of late vasoconstriction (1 microM, 60 min, p = 0.03). The amitriptyline-induced bronchoconstriction was attenuated by the beta(2)-agonist salbutamol (1 microM, 30 min, p = 0.03) and the platelet-activating factor antagonist WEB2086 (10 microM, 30 min, p = 0.03). Staurosporine had an initial protective effect on bronchoconstriction (3 microM, 5 min, p = 0.003), while PD145065 significantly decreased bronchoconstriction 60 min after start of amitriptyline exposure (1 microM, 30 min, p = 0.003). This indicates that endothelin as well as platelet activating factor and protein kinase activation are important in mediating amitriptyline-induced lung function impairment in our experimental model and perhaps also in acute lung injury.

Acute Disease↗
PubMed1988

Non-selectivity of amitriptyline for subtypes of brain muscarinic receptors demonstrated in binding and functional assays.

The characteristics of interaction of amitriptyline, a tricyclic antidepressant, with rat brain muscarinic receptors were assessed using both radioligand binding and functional assays. In competition studies, amitriptyline displaced muscarinic ligand binding from a single high-affinity site in homogenates of various brain regions which have a different distribution of M1 and M2 receptor subtypes. The affinity of amitriptyline for muscarinic receptors was also comparable in all brain regions. Furthermore, amitriptyline identified a single species of muscarinic receptors in intact cells dissociated from the cerebral cortex and in cerebrocortical slices. The non-selectivity of amitriptyline for muscarinic receptor subtypes in these preparations was in contrast to the selectivity exhibited by pirenzepine. This non-selective nature of amitriptyline was also evident in functional assays, since this antidepressant was equipotent at antagonizing M1-mediated increase in phosphoinositide hydrolysis and M2-mediated inhibition of cyclic AMP formation in dissociated cortical cells. Atropine was also equipotent at blocking both responses but was 20- to 30-fold more potent than amitriptyline. These results demonstrate that amitriptyline behaves as a non-selective muscarinic antagonist using both radioligand binding and functional measurements.

Amitriptyline↗
PubMed2004

Piracetam counteracts the effects of amitriptyline on inhibitory avoidance in CD1 mice.

The purpose of the present work was to study the effects of amitriptyline on animal cognition in relation to some characteristics of its therapeutic effects. The modulation of acute and chronic effects of amitriptyline on inhibitory avoidance in male and female mice by piracetam was investigated. In Experiment 1, mice were subjected to the training phase of inhibitory avoidance conditioning 60 min after acute piracetam (100 mg/kg) or physiological saline administration. Immediately after the behavioural task, they received a single injection of the tricyclic antidepressant amitriptyline (30 mg/kg) or physiological saline. Twenty-four hours later, subjects were tested for avoidance. In Experiment 2, the same doses of amitriptyline and piracetam were chronically administered. Mice were subjected to the training phase of inhibitory avoidance on the 22nd day, and to the test phase 24 h later. Forty-five minutes after test, subjects explored the elevated plus-maze for 5 min in order to assess whether the effects of amitriptyline on avoidance performance may reflect general behavioural changes. Results obtained were that: (a) acute and chronic amitriptyline impaired inhibitory avoidance of male and female mice, (b) piracetam counteracted the effect of acutely administered amitriptyline on inhibitory avoidance, and (c) piracetam counteracted the effects of chronically administered amitriptyline in males but not females in the same learning task. These effects do not seem to be mediated by non-specific drug effects on spontaneous motor activity or anxiety.

Amitriptyline↗
PubMed2004

Amitriptyline produces multiple influences on the peripheral enhancement of nociception by P2X receptors.

Peripherally administered amitriptyline exhibits potential to be a locally active analgesic, while ATP augments peripheral nociception by interacting with P2X(3) receptors on sensory afferents. The present study examined the effects of amitriptyline on flinching and biting/licking behaviours and thermal hyperalgesia produced by alphabeta-methylene-ATP (alphabeta-MeATP), a ligand for P2X(3) receptors, following intraplantar administration into the hindpaw of rats. Coadministration of low doses of amitriptyline (up to 100 nmol) with alphabeta-MeATP augmented thermal hyperalgesia and flinching behaviours. The most active dose of amitriptyline (100 nmol) had no intrinsic effect. Augmentation of alphabeta-MeATP actions appears to be due to increased tissue levels of biogenic amines resulting from inhibition of uptake, as phentolamine (alpha(1)/alpha(2)-adrenergic receptor antagonist) and methysergide (5-hydroxytryptamine or 5-HT(1)/5-HT(2) receptor antagonist) inhibit the augmented flinching produced by alphabeta-MeATP/amitriptyline. When noradrenaline and 5-HT were coadministered with alphabeta-MeATP (both increase the effect of alphabeta-MeATP), amitriptyline had no effect on flinching produced by alphabeta-MeATP/noradrenaline but inhibited flinching produced by alphabeta-MeATP/5-HT. In the presence of low concentrations of formalin (0.5%, 1%; which also increase the effect alphabeta-MeATP), amitriptyline inhibited augmented behaviours. Higher doses of amitriptyline (300-1000 nmol) increased thermal thresholds, suppressed thermal hyperalgesia produced by alphabeta-MeATP, and inhibited flinching produced by alphabeta-MeATP. Collectively, these results indicate that amitriptyline produces complex influences on peripheral pain signaling by P2X receptors. Lower doses augment nociception by alphabeta-MeATP (probably by inhibiting noradrenaline and 5-HT uptake) but inhibit alphabeta-MeATP responses in the presence of inflammatory mediators (perhaps reflecting receptor blocking properties); higher doses uniformly inhibit nociception by alphabeta-MeATP (perhaps reflecting local anesthetic properties).

Adenosine Triphosphate↗
PubMed2000

Caffeine blockade of the thermal antihyperalgesic effect of acute amitriptyline in a rat model of neuropathic pain.

In the present study, we sought to determine whether administration of caffeine, a non-selective adenosine receptor antagonist, would affect the thermal antihyperalgesic efficacy of acute amitriptyline in a rat model of neuropathic pain. Rats were rendered neuropathic by unilateral tight ligation of the fifth and sixth lumbar spinal nerves, and tested for thermal hyperalgesia using a focused beam of light. Systemic administration of caffeine (1.5-7.5 mg/kg), at the same time as amitriptyline, blocked the thermal antihyperalgesic effect of 10 mg/kg amitriptyline. The greatest degree of block exerted by caffeine was observed with 3.75 mg/kg (100% block), a dose that had no observable intrinsic effect. Spinal administration of amitriptyline (60 microg) exhibited a mild antihyperalgesic effect that was unaffected by pretreatment with intrathecal caffeine (100 microg). Peripheral administration of amitriptyline into the neuropathic paw (under brief anesthesia) produced an antihyperalgesic effect at both 30 and 100 nmol, with a greater effect being observed at 100 nmol. Coadministration of caffeine (1500 nmol) partially antagonized the effects of both doses of amitriptyline. The results of this study suggest that the thermal antihyperalgesic effect of acute amitriptyline in this model may involve enhancement of an endogenous adenosine tone. This involvement is important in light of the widespread consumption of caffeine, which may potentially act to reduce the benefits of amitriptyline in the treatment of neuropathic pain.

Amitriptyline↗
PubMed1999

Peripheral antinociceptive action of amitriptyline in the rat formalin test: involvement of adenosine.

The present study determined (1) whether amitriptyline could produce a local antinociceptive action in the formalin test, (2) whether endogenous adenosine was involved in this action, and (3) which other systems might contribute to such an action. Coadministration of amitriptyline 10-100 nmol with 2.5% formalin produced a dose-related reduction in phase 1 (0-12 min) and phase 2 (16-60 min) flinching behaviours, as well as in phase 2 biting/licking time (no phase 1 expression). This action was not seen or only partially expressed at low concentrations of formalin (0.5%, 0.75%). Coadministration of caffeine with amitriptyline partially reversed the antinociceptive action of amitriptyline against both behaviours at 2.5% formalin. At 1.5% formalin, caffeine still produced only a partial reversal of effect; this appeared to be due to a block of adenosine A1 receptors, as it was also seen with the selective adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dimethylxanthine. Using antagonists for a number of other systems, no evidence for an involvement of alpha-adrenergic, histamine, excitatory amino acid or opioid receptors in the action of amitriptyline was observed or inferred. A local anaesthetic action for amitriptyline remains a possibility for the residual action. These results indicate that amitriptyline can produce a local peripheral antinociceptive action which is mediated, in part, by an interaction with endogenous adenosine, most likely an inhibition of the cellular uptake of adenosine with a consequent activation of adenosine A1 receptors on sensory nerve terminals. Local application of amitriptyline by cream or gel might prove to be a useful method of drug delivery in inflammatory pain states.

Adenosine↗
PubMed2002

The effects of St John's wort extract on heart rate variability, cognitive function and quantitative EEG: a comparison with amitriptyline and placebo in healthy men.

AIMS: To compare the effects of multiple dosing with St John's wort (Hypericum perforatum) extract and amitriptyline on heart rate variability, cognitive function and quantitative EEG (qEEG) with placebo in healthy humans. METHODS: A randomized, double-blind, cross over study of 12 healthy male volunteers. Subjects orally received capsules with 255-285 mg St John's wort extract (900 micro g hypericin content), 25 mg amitriptyline and placebo three times daily for periods of 14 days each with at least 14 days between. The doses of amitriptyline and St John's wort extract are comparable with respect to their antidepressant activity. Compliance was confirmed by coadministration of 10 mg of riboflavin with each capsule and detection of urinary vitamin B2 on treatment day 11 with high performance liquid chromatography. Measurements of heart rate variability, psychometric tests and qEEG were performed before start of medication and repeatedly on the last treatment day. RESULTS: St John's wort extract did not affect heart rate variability (HRV) whereas amitripytline significantly decreased it: the difference in the percentage number of adjacent RR intervals> 50 ms (pNN50) was 8.6 (-2.6, 19.9; mean; 95% confidence interval) between St John's wort extract and placebo and -17.6 (-24.7, -10.4) between amitriptyline and placebo. Neither St John's wort extract nor amitriptyline had an influence on cognitive performance such as choice reaction, psychomotor coordination, short-term memory and responsiveness to distractive stimuli. Amitriptyline but not St John's wort extract decreased self rated activity (P < 0.05). Both drugs caused significant qEEG changes. St John's wort extract increased theta power density. Amitriptyline increased theta as well as fast alpha power density. CONCLUSIONS: Multiple doses of St John's wort extract do not affect heart rate variability nor cognitive function. Chronic administration of amitriptyline causes a decrement of HRV and subjective sedation but it does not impair cognitive performance.

Adult↗
PubMed1996

Unstable anticoagulation in the course of amitriptyline treatment.

A potential drug-drug interaction between the tricyclic antidepressant amitriptyline and the oral anticoagulant phenprocoumon, causing intensified hypo- and/or hyperprothrombinemic effects, was investigated. In seven patients simultaneously receiving amitriptyline and phenprocoumon the course of the Quick values and the amitriptyline and phenprocoumon dosages were registered. The resulting data represented graphically was additionally compared with data and diagrams gained from a control group of seven phenprocoumon patients not receiving amitriptyline. Whereas in the control group the average Quick values (or the target International Normalized Ratio) lay within the required therapeutic range, massive fluctuations were seen in the amitriptyline-treated patients. These fluctuations did not disappear until the amitriptyline medication was discontinued. Whether our findings are actually due to a clinically relevant drug-drug interaction needs to be investigated in further controlled studies based on a larger number of patients, the more so as no comparable investigations and only few references to this subject are to be found in the literature. Should an amitriptyline influence on the frequently prescribed coumarin derivative be proven, an increased risk of rethrombosis or bleeding complications in patients receiving both amitriptyline and phenprocoumon would appear to be indicated.

Adult↗
PubMed1992

Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy.

BACKGROUND: Amitriptyline reduces the pain caused by peripheral-nerve disease, but treatment is often limited by side effects related to the drug's many pharmacologic actions. Selective agents might be safer and more effective. METHODS: We carried out two randomized, double-blind, crossover studies in patients with painful diabetic neuropathy, comparing amitriptyline with the relatively selective blocker of norepinephrine reuptake desipramine in 38 patients, and comparing the selective blocker of serotonin reuptake fluoxetine with placebo in 46 patients. Fifty-seven patients were randomly assigned to a study as well as to the order of treatment, permitting comparison among all three drugs and placebo as the first treatment. The patients rated the degree of pain present each day using verbal descriptors, and they also assessed the extent of pain relief globally at the end of each treatment period. RESULTS: After individual dose titration, the mean daily doses of the drugs were as follows: amitriptyline, 105 mg; desipramine, 111 mg; and fluoxetine, 40 mg. There was moderate or greater relief of pain in 28 of the 38 patients (74 percent) who received amitriptyline, 23 of the 38 patients (61 percent) who received desipramine, 22 of the 46 patients (48 percent) who received fluoxetine, and 19 of the 46 patients (41 percent) who received placebo. The differences in responses between amitriptyline and desipramine and between fluoxetine and placebo were not statistically significant, but both amitriptyline and desipramine were superior to placebo. Amitriptyline and desipramine were as effective in patients who were not depressed as in depressed patients, but fluoxetine was effective only in depressed patients. CONCLUSIONS: Desipramine relieves pain caused by diabetic neuropathy with efficacy similar to that of amitriptyline, offering an alternative for patients unable to tolerate the latter. Blockade of norepinephrine reuptake is likely to mediate the analgesic effect of these antidepressant drugs in diabetic neuropathy. Fluoxetine, which blocks serotonin uptake, is no more effective than placebo for the relief of pain.

Adult↗
PubMed2002

The interaction between gabapentin and amitriptyline in the rat formalin test after systemic administration.

UNLABELLED: We examined the effects of systemically administered gabapentin on flinching and biting/licking behaviors produced by 2.5% formalin in the rat, compared these with those of amitriptyline, and determined the effects of combinations of gabapentin with amitriptyline. Gabapentin produced a dose-related inhibition of Phase 2, but not Phase 1, flinching and biting/licking behaviors. In contrast, amitriptyline produced an increase in Phase 2 flinching behaviors while simultaneously decreasing biting/licking behaviors. Fifty percent effective dose (ED50) values against biting/licking behaviors were 22.9 +/- 1.3 mg/kg and 8.5 +/- 1.3 mg/kg for gabapentin and amitriptyline, respectively. Combinations of increasing fractional increments of ED50 doses of gabapentin and amitriptyline produced an additive effect against biting/licking behaviors, as revealed by isobolographic analysis. These increments had no effect on flinching behaviors except at the ED25 + ED25 doses, at which flinching was increased, again revealing additivity between the two drugs. Flinching behaviors in rats do not reflect the analgesic properties of systemically administered amitriptyline observed in humans and may not be useful for predicting an effect of combinations of drugs with amitriptyline. Biting/licking behaviors do reflect analgesic properties for both drugs and may be more useful in this regard. IMPLICATIONS: By use of the rat formalin test, a model of persistent pain, we examined the effect of a combination of amitriptyline and gabapentin, which are used to treat chronic pain in humans. The drug combination produced additive analgesia against one outcome, but another outcome was more ambiguous.

Acetates↗
PubMed1997

Alfentanil, but not amitriptyline, reduces pain, hyperalgesia, and allodynia from intradermal injection of capsaicin in humans.

BACKGROUND: Intradermal injection of capsaicin produces brief pain followed by hyperalgesia and allodynia in humans, and the latter effects are mediated by spinal N-methyl-D-aspartate mechanisms. Amitriptyline recently was shown to antagonize N-methyl-D-aspartate receptors, and in this study, the authors sought to determine the effect of amitriptyline alone and with the opioid alfentanil on hyperalgesia and allodynia produced by intradermal injection of capsaicin. METHODS: Forty-six healthy volunteers in the general clinical research center received repeated intradermal injections of capsaicin (100 microg) alone or before and after systemic injection of 4 mg midazolam, 25 mg amitriptyline, alfentanil by computer-controlled infusion, or amitriptyline plus alfentanil. Acute pain and areas of mechanical hyperalgesia and allodynia were determined at specified intervals. Blood was obtained for alfentanil and amitriptyline assay. RESULTS: Capsaicin injection produced acute pain followed by hyperalgesia and allodynia. Alfentanil reduced these pain responses in a plasma-concentration-dependent manner, and reduction in hyperalgesia and allodynia correlated with reduction in acute pain. Amitriptyline alone had no effect and did not potentiate alfentanil. Alfentanil produced concentration-dependent nausea, an effect diminished by amitriptyline. DISCUSSION: These data correspond with previous studies in volunteers demonstrating reduction in hyperalgesia and allodynia after intradermal injection of capsaicin by systemically administered opioids, and they suggest that this reduction may be secondary to reduced nociceptive input by acute analgesia. These data do not support the use of acute systemic administration of amitriptyline for acute pain, hyperalgesia, and allodynia, although the roles of chronic treatment and spinal administration are being investigated.

Adult↗
PubMed2002

N-phenylethyl amitriptyline in rat sciatic nerve blockade.

BACKGROUND: The antidepressant amitriptyline is commonly used orally for the treatment of chronic pain, particularly neuropathic pain, which is thought to be caused by high-frequency ectopic discharge. Among its many properties, amitriptyline is a potent Na(+) channel blocker in vitro, has local anesthetic properties in vivo, and confers additional blockade at high stimulus-discharge rates (use-dependent blockade). As with other drug modifications, adding a phenylethyl group to obtain a permanently charged quaternary ammonium derivative may improve these advantageous properties. METHODS: The electrophysiologic properties of N-phenylethyl amitriptyline were assessed in cultured neuronal GH(3) cells with the whole cell mode of the patch clamp technique, and the therapeutic range and toxicity were evaluated in the rat sciatic nerve model. RESULTS: In vitro, N-phenylethyl amitriptyline at 10 microm elicits a greater block of Na(+) channels than amitriptyline (resting block of approximately 90% vs. approximately 15%). This derivative also retains the attribute of amitriptyline in evoking high-degree use-dependent blockade during repetitive pulses. In vivo, duration to full recovery of nociception in the sciatic nerve model was 1,932 +/- 72 min for N-phenylethyl amitriptyline at 2.5 mm (n = 7) versus 72 +/- 3 min for lidocaine at 37 mm (n = 4; mean +/- SEM). However, there was evidence of neurotoxicity at 5 mm. CONCLUSION: N-phenylethyl amitriptyline appears to have a narrow therapeutic range but is much more potent than lidocaine, providing a block duration several times longer than any clinically used local anesthetic. Further work in animal models of neuropathic pain will assess the potential use of this drug.

Amitriptyline↗
PubMed2004

Synergistic antinociceptive effect of amitriptyline and morphine in the rat orofacial formalin test.

BACKGROUND: Combination therapy is often used to increase the clinical utility of analgesic agents. The coadministration of two compounds may achieve analgesia at doses lower than those required for either compound alone, leading to enhanced pain relief and reduction of adverse effects. Herein, the authors describe the effect of coadministration of morphine and amitriptyline on cutaneous orofacial inflammatory pain in rats. METHODS: Amitriptyline, morphine, or the combination of amitriptyline and morphine was administered systemically to rats, and antinociceptive effects were determined by means of the rat orofacial formalin test. Isobolographic analysis was used to define the nature of the interactions between morphine and amitriptyline. RESULTS: Amitriptyline as well as morphine produced a dose-related inhibition in the first phase and the second phase of rubbing activity. ED50 values against rubbing behavior were 14.6 mg/kg (95% confidence interval, 10.2-33.5 mg/kg) and 1.3 mg/kg (95% confidence interval, 1.0-1.7 mg/kg) for amitriptyline and morphine, respectively. Combinations of increasing fractional increments of amitriptyline and morphine ED50 doses produced a synergistic effect against rubbing behavior, as revealed by isobolographic analysis. CONCLUSIONS: The current study suggests that systemic amitriptyline and morphine synergistically inhibit cutaneous orofacial inflammatory pain in rats.

Amitriptyline↗
PubMed2004

Amitriptyline neurotoxicity: dose-related pathology after topical application to rat sciatic nerve.

BACKGROUND: Amitriptyline is a tricyclic antidepressant drug used systemically for the management of neuropathic pain. Antidepressants, as a class of drugs with direct neurologic actions, are becoming widely used for the management of chronic pain, although their mechanisms are not entirely understood. Amitriptyline exerts potent effects on reuptake of norepinephrine and serotonin and blocks alpha 2A adrenoreceptors and N-methyl-D-aspartate receptors. Because amitriptyline is also a particularly potent blocker of sodium channels and voltage-gated potassium and calcium channels, it has been recommended as a long-acting local anesthetic agent. Unfortunately, amitriptyline has significant toxic side effects in the central nervous system and cardiovascular system that are dose-related to its systemic administration. Therefore, before amitriptyline can be used clinically as a local anesthetic agent, it should be thoroughly explored with respect to its direct neurotoxic effect in the peripheral nervous system. METHODS: The left sciatic nerve of Sprague-Dawley rats (12/ group) received a single topical amitriptyline dose of 0.625, 1.25, 2.5, or 5 mg; a saline group (n = 2) was used as control. Neuropathologic evaluations were conducted in separate animals (n = 4) 1, 3, and 7 days later. RESULTS: Amitriptyline topically applied in vivo to rat sciatic nerve causes a dose-related neurotoxic effect. Drug doses of 0.625-5 mg all caused Wallerian degeneration of peripheral nerve fibers, with the number of affected fibers and the severity of the injury directly related to the dose. CONCLUSION: Because the effective local anesthetic dose is within this dose range, the authors strongly recommend that amitriptyline not be used as a local anesthetic agent.

Administration, Topical↗
PubMed2002

Decreased plasma levels of amitriptyline and its metabolites on comedication with an extract from St. John's wort ( Hypericum perforatum ).

Extracts of St. John's wort ( Hypericum perforatum ) became increasingly popular as easily available remedies for mild to moderate depression. Comedication with hypericum extract was recently shown to drastically reduce plasma concentration of ciclosporin, digoxin, and indinavir. We investigated the possible interaction of hypericum extract LI160 with amitriptyline. Both antidepressants have a high probability of concomitant use. Twelve patients requiring amitriptyline treatment received a single dose of hypericum extract (900 mg) at day 1, continued by a 12-to 14-day treatment with retarded amitriptyline (75 mg twice daily). Then hypericum (900 mg/day) was added for another 14 to 16 days. Steady-state pharmacokinetics of amitriptyline were compared before and after multiple-dose treatment with hypericum extract. Furthermore, comparisons were made for single-dose kinetics of hypericum-extract ingredients hypericin, pseudohypericin, and hyperforin between the first day of concomitant treatment and LI160 alone. Multiple-dose comedication with LI160 led to a statistically significant decrease in the area under the plasma concentration-time curve within one dosing interval of amitriptyline by 22% ( p = 0.03) and nortriptyline by 41% ( p = 0.002), as well as of all hydroxylated metabolites, except for 10-E-hydroxynortriptyline. Plasma levels of amitriptyline and hydroxylated metabolites gradually decreased, whereas nortriptyline concentrations were already markedly decreased after 3 days of cotreatment with hypericum. Cumulative urinary amounts of amitriptyline and metabolites decreased to the same extent as plasma concentrations upon hypericum comedication. Induction of cytochrome P-450 enzymes or drug transporters (P-glycoprotein) by St. John's wort extract may explain this pharmacokinetic interaction. Physicians should be aware of this interaction when treating patients with amitriptyline.

Adult↗
PubMed1993

Fluoxetine versus amitriptyline in the treatment of major depression: a multicenter trial.

Fluoxetine, a serotonin uptake inhibitor, and amitriptyline, a tricyclic antidepressant, were compared in a 5-week, multicenter, double-blind, randomized trial in 136 out-patient men and women, aged 21-70 years, with major depressive disorder. Overall efficacy was comparable with fluoxetine and amitriptyline [Hamilton 21-Item Rating Scale for Depression (HAM-D21), Raskin, Covi, Clinical Global Impressions-Severity and -Improvement, Patient's Global Impressions]. Mean +/- standard deviation decreases in HAM-D21 total score were 12.9 +/- 9.9 and 11.6 +/- 10.3 (p = 0.423), respectively. Response rates (> or = 50% decrease in HAM-D21 total score) for patients treated > or = 4 weeks were 46.7% and 66.0% (p = 0.039) and remission rates (HAM-D21 total score < or = 7) were 18.3% and 28.3% (p = 0.209), respectively. Response and remission rates for all patients were comparable with fluoxetine and amitriptyline. Study completions were higher with fluoxetine than amitriptyline (87.7% vs 66.2%; p = 0.003). Discontinuations for adverse events were higher with amitriptyline than fluoxetine (22.5% vs 6.2%; p = 0.007). More treatment-emergent nausea and insomnia were reported with fluoxetine (p < or = 0.05); more anticholinergic and orthostatic events and weight gain were reported with amitriptyline (p < or = 0.05). Statistically, but not clinically, significant changes were observed in vital signs. Both fluoxetine and amitriptyline were effective treatments for out-patients with major depressive disorder. Fluoxetine had a more favorable safety profile than amitriptyline.

Adult↗
PubMed1998

Mirtazapine versus amitriptyline in the long-term treatment of depression: a double-blind placebo-controlled study.

Of 580 patients randomly assigned to short-term, double-blind treatment with either mirtazapine, amitriptyline or placebo, a total of 217 patients clinically judged to be responders subsequently continued on the same medication for up to 2 years in the long-term treatment study (mirtazapine, n = 74; amitriptyline, n = 86 and placebo, n = 57). The efficacy of mirtazapine in relapse prevention was seen in an analysis of the first 20 weeks data. Significantly fewer patients relapsed during treatment with mirtazapine compared with placebo (p < 0.05), and a significantly longer time to relapse was shown on the survival analysis. There was a significant advantage for amitriptyline compared with placebo in the first 20 weeks, with fewer patients relapsing. There was a significant advantage for mirtazapine compared with amitriptyline at 20 weeks seen on the survival analysis (p < 0.05). The significant advantage for mirtazapine compared with placebo was also seen in the prophylactic phase of treatment after 20 weeks. At the endpoint there were significantly more patients in the placebo group with a return of symptoms and significantly fewer showing sustained response. Amitriptyline was better than placebo with fewer patients suffering a recurrence of symptoms, but there was no difference from placebo in the proportion of patients with sustained response. Mirtazapine was well tolerated with a side-effect profile similar to that of placebo. The only adverse event reported significantly more frequently on mirtazapine than on placebo was weight gain. Objectively measured weight gain was more frequent with amitriptyline (22% of patients) compared with mirtazapine (13% of patients). Amitriptyline was associated with significantly more adverse events than either mirtazapine or placebo, in particular sedative and anticholinergic side effects. The efficacy of mirtazapine in reducing the risk of relapse and the recurrence of depression, which on some measures showed an advantage compared with amitriptyline, coupled with its improved side-effect profile, commends this antidepressant for the long-term treatment of depression.

Adolescent↗
PubMed1991

Amitriptyline-mediated inhibition of neurite outgrowth from chick embryonic cerebral explants involves a reduction in adenylate cyclase activity.

We have previously shown that amitriptyline, a tricyclic antidepressant, inhibited neurite outgrowth from chick embryonic cerebral explants, and that dibutyryl cyclic AMP, 3-isobutyl-1-methylxanthine, or theophylline can enhance neurite outgrowth from embryonic olfactory explants. In the present study, we examined the mechanism(s) underlying amitriptyline-mediated inhibition of neurite outgrowth by studying the effects of amitriptyline on adenylate cyclase activity and cyclic AMP levels. In cultured chick embryonic cerebral explants, dibutyryl cyclic AMP or theophylline, but not dibutyryl cyclic GMP, enhanced neurite outgrowth and partially reduced the inhibitory effects of amitriptyline on neurite outgrowth. Explants treated with amitriptyline for 2 days showed decreased cyclic AMP levels that significantly correlated with the degree of neurite outgrowth. Amitriptyline inhibited both basal and forskolin-stimulated adenylate cyclase activity in vitro, but only in the presence of GTP. Taken together, these data suggest that amitriptyline inhibits the activity of adenylate cyclase via a GTP-dependent mechanism, and that the subsequent decrease in cyclic AMP level may be involved in amitriptyline-mediated inhibition of neurite outgrowth.

Adenylyl Cyclases↗